Identifying agents to treat alzheimer's disease-related decreased sorting behavior by administration to a triple transgenic mouse expressing mutant forms of APP, presenilin or tau
The method of the invention is useful for evaluating pharmaceutical compositions for treatment of neurological diseases encompassing neurological or neurodegenerative diseases associated with cognitive dysfunction and, in particular, dementia; schizophrenia; anxiety; depression; and pain using a rodent behavioral assay, wherein the method is useful in testing compositions useful in the modulation, amelioration, prevention, or treatment of dementia using a non-human animal carrying at least a transgene for human amyloid-beta protein or human tau and transgenes causing the elevated production of the human amyloid-beta protein in the animal as compared to nontransgenic animals of the same genetic background and the behavior is a nesting behavior.
1. A method of identifying and selecting an agent for use in the prevention, treatment, or amelioration of a condition selected from the group consisting of Alzheimer's disease and a tau pathology, using a transgenic mouse whose genome comprises mutant nucleic acids that encode the Swedish mutant form of human amyloid precursor protein (hAPP), the PS1 M146V mutant form of presenilin-1, and the P301L mutant form of tau, wherein the transgenic mouse exhibits decreased sorting behavior compared to a non-transgenic mouse of the same strain, the method comprising the steps of:
a) providing a number of said transgenic mice;
b) dividing the mice into a test group and a control group and providing each with sortable material;
c) administering a test agent to mice in said test group and administering a control agent to mice in said control group;
d) observing the mice in said test group and said control group for sorting behavior;
e) assessing the sorting behavior, wherein a decrease in sorting behavior in the test group, as compared to the control group, is indicative of Alzheimer's disease or a tau pathology, and an increase in sorting behavior in the test group, as compared to the control group, is indicative of amelioration of symptoms associated with Alzheimer's disease or a tau pathology; and
f) selecting a test agent that produces an increase in sorting behavior in the test group, as compared to the control group, as an agent for trestment of Alzheimer's disease or a tau pathology.
2. The method of claim 1 wherein a reduction in sorting behavior is coincident with a histopathological marker present in the transgenic mice.
3. The method of claim 2 wherein the severity of the histopathological marker produces a phenotype that is decreased coincident with the exhibition of an increase in sorting behavior in the transgenic mice.
4. The method of claim 2 wherein the histopathological marker is selected from the group consisting of compacted plaques, neuritic dystrophy, gliosis, A-beta deposits, decreased synaptic density, and synaptic abnormalities.
5. The method of claim 1 , wherein a predetermined scoring system is applied to each observation of the sorting behavior and the scores obtained using said scoring system are subjected to statistical analysis to determine whether the differences in sorting behavior between test and control groups is statistically significant.
6. The method of claim 1 , wherein the test agent comprises a substance selected from the group consisting of an antibody, a fusion protein, a therapeutic protein, a small-molecule neuroactive, an antidiabetic agent, an oligonucleotide, and a dietary supplement.